Sanz-Ros Jorge, Mas-Bargues Cristina, Romero-García Nekane, Huete-Acevedo Javier, Dromant Mar, Borrás Consuelo
Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, Valencia 46010, Spain.
Department of Cardiology, Hospital Universitari i Politècnic La Fe, Valencia 46026, Spain.
Extracell Vesicles Circ Nucl Acids. 2023 Aug 18;4(3):486-501. doi: 10.20517/evcna.2023.29. eCollection 2023.
Aging is characterized by genomic instability and dysregulation of gene expression. MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in post-transcriptional gene regulation. This work explores the impact of dysregulated miRNA biogenesis on the aging process. During aging, alterations in the transcription of primary miRNAs (pri-miRNAs) occur due to genomic changes, DNA damage, and epigenetic modifications. The microprocessor complex, comprising DGCR8 and Drosha proteins, is vital for pri-miRNA processing. Age-related changes in this complex affect miRNA biogenesis and miRNA expression profiles, linking these alterations with age-related conditions. Conversely, interventions like caloric restriction and mTOR inhibition enhance microprocessor activity, suggesting a connection between microprocessor function, aging-related pathways, and lifespan extension. Exportin-5 mediates the transport of pre-miRNAs from the nucleus to the cytoplasm. Although the role of miRNA export in aging is not well understood, accelerated export of pre-miRNAs is observed in response to DNA damage, and nucleocytoplasmic transport has been linked to cellular senescence. Dicer is responsible for processing pre-miRNAs into mature miRNAs. Reduced Dicer expression during aging is reported in various organisms and tissues and is associated with premature aging phenotypes. Conversely, the upregulation of Dicer improves stress resistance and metabolic adaptations induced by caloric restriction and exercise training. Understanding the role of miRNA biogenesis disruption in aging provides insights into the molecular mechanisms of aging and age-related diseases. Targeting this pathway may hold promise for therapeutic strategies and contribute to healthy aging.
衰老的特征是基因组不稳定和基因表达失调。微小RNA（miRNA）是一类小的非编码RNA，在转录后基因调控中发挥关键作用。这项工作探讨了失调的miRNA生物合成对衰老过程的影响。在衰老过程中，由于基因组变化、DNA损伤和表观遗传修饰，初级miRNA（pri-miRNA）的转录会发生改变。由DGCR8和Drosha蛋白组成的微处理器复合体对pri-miRNA的加工至关重要。该复合体中与年龄相关的变化会影响miRNA的生物合成和miRNA表达谱，将这些改变与年龄相关的状况联系起来。相反，热量限制和mTOR抑制等干预措施会增强微处理器的活性，这表明微处理器功能、衰老相关途径和寿命延长之间存在联系。Exportin-5介导前体miRNA从细胞核向细胞质的转运。尽管miRNA输出在衰老中的作用尚未完全了解，但在DNA损伤时会观察到前体miRNA的加速输出，并且核质运输与细胞衰老有关。Dicer负责将前体miRNA加工成成熟的miRNA。在各种生物体和组织中都有报道，衰老过程中Dicer表达降低，并且与早衰表型相关。相反，Dicer的上调可提高热量限制和运动训练诱导的抗应激能力和代谢适应性。了解miRNA生物合成破坏在衰老中的作用有助于深入了解衰老和年龄相关疾病的分子机制。针对这一途径可能为治疗策略带来希望，并有助于实现健康衰老。
